Epileptiform activity and cognitive deficits in SNAP-25(+/-) mice are normalized by antiepileptic drugs.

Synaptosomal-associated protein of 25 kDa (SNAP-25) is a protein that participates in the regulation of synaptic vesicle exocytosis through the formation of the soluble NSF attachment protein receptor complex and modulates voltage-gated calcium channels activity. The Snap25 gene has been associated with schizophrenia, attention deficit hyperactivity disorder, and bipolar disorder, and lower levels of SNAP-25 have been described in patients with schizophrenia. We used SNAP-25 heterozygous (SNAP-25(+/-)) mice to investigate at which extent the reduction of the protein levels affects neuronal network function and mouse behavior. As interactions of genotype with the specific laboratory conditions may impact behavioral results, the study was performed through a multilaboratory study in which behavioral tests were replicated in at least 2 of 3 distinct European laboratories. Reductions of SNAP-25 levels were associated with a moderate hyperactivity, which disappeared in the adult animals, and with impaired associative learning and memory. Electroencephalographic recordings revealed the occurrence of frequent spikes, suggesting a diffuse network hyperexcitability. Consistently, SNAP-25(+/-) mice displayed higher susceptibility to kainate-induced seizures, paralleled by degeneration of hilar neurons. Notably, both EEG profile and cognitive defects were improved by antiepileptic drugs. These results indicate that reduction of SNAP-25 expression is associated to generation of epileptiform discharges and cognitive dysfunctions, which can be effectively treated by antiepileptic drugs.

Mapping the transverse coherence of the self amplified spontaneous emission of a free-electron laser with the heterodyne speckle method.

The two-dimensional single shot transverse coherence of the Self-Amplified Spontaneous Emission of the SPARC_LAB Free-Electron Laser was measured through the statistical analysis of a speckle field produced by heterodyning the radiation beam with a huge number of reference waves, scattered by a suspension of particles. In this paper we report the measurements and the evaluation of the transverse coherence along the SPARC_LAB undulator modules. The measure method was demonstrated to be precise and robust, it does not require any a priori assumptions and can be implemented over a wide range of wavelengths, from the optical radiation to the x-rays.

Learning and memory impairment induced by salvinorin A, the principal ingredient of Salvia divinorum, in wistar rats.

The effects of salvinorin A (Salvia divinorum principal ingredient), a potent κ-opioid natural hallucinogen, on learning and memory were investigated. Wistar rats were tested in the 8-arm radial maze, for object recognition and passive avoidance tasks for spatial, episodic, and aversive memory. Attention was assessed using a latent inhibition task. Salvinorin A (80-640 µg/kg subcutaneous [sc]) did not affect short-term memory, but it impaired spatial long-term memory. Episodic and aversive memories were impaired by salvinorin A (160-640 µg/kg). Memory impairment was blocked by the selective κ-opioid receptor antagonist, nor-binaltorphimine ([nor-B]; 0.5-1 mg/kg, intraperitoneal [ip]). Salvinorin A (160 µg/kg) disrupted latent inhibition, after LiCl treatment, such as reduced sucrose intake, suggesting an attention would result in an impairment of cognitive behavior. These findings demonstrate for the first time that salvinorin A has deleterious effects on learning and memory, through a κ-opioid receptor mechanism.

Spontaneous object and movement representations in 4-month-old human infants and albino Swiss mice.

Can young infants decompose visual events into independent representations of objects and movements? Previous studies suggest that human infants may be born with the notion of objects but there is little evidence for movement representations during the first months of life. We devised a novel Rapid Visual Recognition Procedure to test whether the nervous system is innately disposed for the conceptual decomposition of visual events. We show that 4-month-old infants can spontaneously build object and movement representations and recognize these in partially matching test events. Also albino Swiss mice that were tested on a comparable procedure could spontaneously build detailed mental representations of moving objects. Our results dissociate the ability to conceptually decompose physical events into objects and spatio-temporal relations from various types of human and non-human specific experience, and suggest that the nervous system is genetically predisposed to anticipate the representation of objects and movements in both humans and non-human species.

A new model to study visual attention in zebrafish.

The major part of cognitive tasks applied to zebrafish has not fully assessed their attentional ability, a process by which the nervous system learns, organizes sensory input and generates coordinated behaviour. In an attempt to maximize the value of zebrafish as an animal model of cognition, we tested the possibility to apply a modified version of novel object recognition test named virtual object recognition test (VORT) using 2D geometrical shapes (square, triangle, circle, cross, etc.) on two iPod 3.5-inch widescreen displays, located on two opposite walls of the water tank. Each fish was subjected to a familiarization trial (T1), and after different time delays (from 5 min to 96 h) to a novel shape recognition trial (T2). A progressive decrease, across time, of memory performance, in terms of mean discrimination index and mean exploration time, was shown. The predictive validity was tested using cholinergic drugs. Nicotine (0.02 mg/kg intraperitoneally, IP) significantly increased, while scopolamine (0.025 mg/kg IP) and mecamylamine decreased, mean discrimination index. Zebrafish discriminated different movements (vertical, horizontal, oblique) and the discrimination index increased significantly when moving poorly discriminated shapes were presented, thus increasing visual attention. Taken together these findings demonstrate that VORT is a viable, fast and useful model to evaluate sustained attention in zebrafish and for predicting the efficacy of pharmacotherapies for cognitive disorders.

Role of neuronal nicotinic acetylcholine receptors (nAChRs) on learning and memory in zebrafish.

RATIONALE: Neuronal nicotinic acetylcholine receptors (nAChRs) play a modulatory role in cognition, and zebrafish provide a preclinical model to study learning and memory. OBJECTIVES: We investigated the effect of nicotine (NIC) and some new cytisine-derived partial agonists (CC4 and CC26) on spatial memory in zebrafish using a rapid assay on T-maze task. The role of α4/α6ß2 and the α7 nAChRs in NIC-induced memory enhancement was evaluated using selective nAChR antagonists. RESULTS: Low and high doses of NIC, cytisine (CYT), CC4 and CC26 respectively improved and worsened the mean running time, showing an inverted U dose-response function. The effective dose (ED50) (×10⁻5 mg/kg) was 0.4 for CC4, 4.5 for CYT, 140 for NIC and 200 for CC26. NIC-induced cognitive enhancement was reduced by the selective nAChR subtype antagonists: methyllycaconitine (MLA) for α7, α-conotoxin (MII) for α6ß2, dihydro-ß-erythroidine (DhßE) for α4ß2, the nonselective antagonist mecamylamine (MEC) and the muscarinic antagonist scopolamine (SCOP), with DhßE being more active than MLA or MII. All the partial agonists blocked the cognitive enhancement. The improvement with the maximal active dose of each partial agonist was blocked by low doses of DhßE (0.001 mg/kg) and MII (0.01 mg/kg). MLA reduced the effects of CC26 and CC4 at doses of 0.01 and 1 mg/kg, respectively, but did not antagonize CYT-induced memory improvement at any of the tested dose. No change in swimming activity was observed. CONCLUSIONS: Our findings demonstrate that zebrafish make a useful model for the rapid screening of the effect of new α4ß2 nAChR compounds on spatial memory.

Mice discriminate between stationary and moving 2D shapes: application to the object recognition task to increase attention.

Selective attention can be assessed with the novel object recognition (NOR) test. In the standard version of this test the selection of objects to be used is critical. We created a modified version of NOR, the virtual object recognition test (VORT) in mice, where the 3D objects were replaced with highly discriminated geometrical shapes and presented on two 3.5-inch widescreen displays. No difference in the discrimination index (from 5min to 96h of inter-trial) was found between NOR and VORT. Scopolamine and mecamylamine decreased the discrimination index. Conversely, the discrimination index increased when nicotine was given to mice. No further improvement in the discrimination index was observed when nicotine was injected in mice presented with highly discriminable shapes. To test the possibility that object movements increased mice's attention in the VORT, different movements were applied to the same geometrical shapes previously presented. Mice were able to distinguish among different movements (horizontal, vertical, oblique). Notably, the shapes previously found not distinguishable when stationary were better discriminated when moving. Collectively, these findings indicate that VORT, based on virtual geometric simple shapes, offers the possibility to obtain rapid information on amnesic/pro-amnestic potential of new drugs. The introduction of motion is a strong cue that makes the task more valuable to study attention.

Neurohypophyseal hormones protect against pentylenetetrazole-induced seizures in zebrafish: role of oxytocin-like and V1a-like receptor.

Oxytocin (OT) and arginine-vasopressin (AVP) are involved in the physiological response to different stressors like the occurrence of seizures which is regarded as a severe stress factor. Zebrafish (Danio rerio) is recently featured as a model of epilepsy but the role of neurohypophyseal hormones on this teleost is still unknown. We attempted to determine whether non-mammalian homologues like isotocin (IT) and vasotocin (AVT) affected pentylenetetrazole (PTZ)-induced seizures in adult zebrafish in comparison with OT/AVP. The mechanism was studied using the most selective OT and AVP receptor antagonists. Zebrafish were injected i.m. with increasing doses (0.1-40 ng/kg) of the neuropeptides 10 min before PTZ exposure. DesGly-NH2-d(CH2)5-[D-Tyr2,Thr4]OVT (desglyDTyrOVT) for OT receptor and SR49059 for V1a subtype receptor, were injected together with each agonist 20 min before PTZ exposure. All the peptides significantly decreased the number of seizures, increased the mean latency time to the first seizure and decreased lethality. This protective effect led to a dose-response curve following a U-shaped form. IT was approximately 40 times more active than OT while AVT was 20 times more potent than AVP in reducing the number of seizures. DesglyDTyrOVT was more effective in antagonizing OT/IT, while SR49059 mainly blocked AVP/AVT-induced protection against PTZ-induced seizures. The present findings provide direct evidence of an important involvement of IT/OT and AVP/AVT as anticonvulsant agents against PTZ-induced seizures with a receptor-mediated mechanism in zebrafish. These data reinforce zebrafish as an emerging experimental model to study and identify new antiepileptic drugs.

Neurohypophyseal hormones manipulation modulate social and anxiety-related behavior in zebrafish.

RATIONALE: Oxytocin (OT) and arginine-vasopressin (AVP) regulate social behavior in mammals. Zebrafish (Danio rerio) allows higher throughput and ease in studying human brain disorders. OBJECTIVES: This study investigated in zebrafish the effect of non-mammalian homologs isotocin (IT) and vasotocin (AVT) in comparison with OT/AVP on social behavior and fear response to predator. The mechanism was studied using the most human selective OT and AVP receptor antagonists. METHODS: Zebrafish were injected i.m. with increasing doses (0.001-40 ng/kg) of the neuropeptides. DesGly-NH(2)-d(CH(2))(5)-[D-Tyr(2),Thr(4)]OVT) for OT receptor, SR 49059 for V1a subtype receptor, and SSR-149415 for V1b subtype receptor were injected i.m. 10 min before each agonist. RESULTS: All the peptides increased social preference and reduced fear to predator response in a dose-dependent manner interpolated by symmetrical parabolas. AVT/AVP were more potent to elicit anxiolytic than social effect while IT and OT were equally potent. All the antagonists dose-dependently inhibited both the effects induced by the neuropeptides. The ratio between the ED50 obtained for blocking the OT-induced effects on social preference and fear response to predator was very high only for desglyDTTyrOVT (160). SR49059 showed the highest ratio in blocking AVP-induced effects (807). The less selective antagonist appeared to be SSR149415. CONCLUSIONS: For the first time, IT/AVT and OT/AVP were found to modulate in zebrafish, social behavior, unrelated to sex, and fear to predator response through at least two different receptors. Zebrafish is confirmed as a valid, reliable model to study deficit in social behavior characteristic of some psychiatric disorders.